As a board-certified VA anesthesiologist and cardiovascular physiologist I study protective mechanisms against ischemia/reperfusion (IR) injury ultimately geared to help our often multi-morbid patients. Veterans frequently suffer from atherosclerosis, including coronary artery disease, and, therefore, have a high incidence of myocardial infarction, with often debilitating functional consequences if surviving. Paradoxically, abrupt reperfusion, i.e., reintroduction of blood flow after prolonged ischemia, and its concomitant molecular and metabolic changes may be more detrimental than the injury caused by the initial ischemia itself. Accordingly, our revised application focuses on mitigating myocardial IR injury by administration of known and newly designed synthetic copolymer-based cell membrane stabilizers (CCMS) given on reperfusion, and on elucidating their protective mechanisms of action. For this original area in cardiovascular research, we propose to use: 1) individual cell cultures and co-cultures of coronary artery endothelial cells and cardiomyocytes; and 2) an isolated, intact heart preparation of myocardial infarction. These will complement each other in focusing on novel mechanisms of myocardial protections by CCMS. Our inter-disciplinary research team from anesthesiology, physiology, and chemical engineering brings together expertise with a wide spectrum of scientific qualifications that combine fields of basic science and medicine that normally have minimal to no interaction in translational research. As such, we are uniquely positioned to enhance our understanding of the complex pathophysiological processes that take place during and after prolonged myocardial IR and to find innovative ways to increase survival, functional recovery and quality of life in thousands of critically ill patients each year. Thus, findings from this highly innovative project may result in novel treatments for victims of heart attacks and may have important implications on the optimal medical care for patients, especially in our vulnerable Veteran population.